ArticleAmerican journal of human genetics2010
Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability.
Article in American journal of human genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00478712 (Genetic Analysis of Hirschsprung Disease), which is not on this map. Cited by 135 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Genetic Analysis of Hirschsprung Disease
Who cites it
135 citing papers in PubMed, 2 syntheses or guidelines pooled it, 243 citations in OpenAlex.
- Transitional care and clinical management of adolescents, young adults, and suspected new adult patients with congenital central hypoventilation syndrome.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2023Pooled it
- The association between Hirschsprung's disease and multiple endocrine neoplasia type 2a: a systematic review.Pediatric surgery international · 2014Pooled it
- Mechanisms underlying disease-causing variants in promoters and enhancers.Nature genetics · 2026Review
- Unraveling the molecular basis of clinical heterogeneity in Hirschsprung disease through gene expression analysis.Pediatric surgery international · 2026Observational
- Whole Genome Sequencing Reveals amedRxiv : the preprint server for health sciences · 2026Article
- Mapping epigenetic gene variant dynamics: comparative analysis of frequency, functional impact and trait associations in African and European populations.Scientific reports · 2026Article
- Variability in proliferative and migratory defects in Hirschsprung disease-associated RET pathogenic variants.American journal of human genetics · 2025Article
- Association of the RET Intronic Variant rs2435357 on Hirschsprung's Disease Susceptibility: A Systematic Review and Meta-Analysis.Iranian journal of public health · 2025Review
- The Role ofmedRxiv : the preprint server for health sciences · 2025Article
- Variability in proliferative and migratory defects in Hirschsprung disease-associatedbioRxiv : the preprint server for biology · 2024Article
- RET enhancer haplotype-dependent remodeling of the human fetal gut development program.PLoS genetics · 2023Article
- Hirschsprung disease.Nature reviews. Disease primers · 2023Review
- mRNA sequencing provides new insights into the pathogenesis of Hirschsprung's disease in mice.Pediatric surgery international · 2023Article
- Transcriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation.Nature communications · 2023Article
- Up-Regulation of microRNA-424 Causes an Imbalance in AKT Phosphorylation and Impairs Enteric Neural Crest Cell Migration in Hirschsprung Disease.International journal of molecular sciences · 2023Article
- Genetics of Hirschsprung's disease.Pediatric surgery international · 2023Review
- A genome-wide association study identifies distinct variants associated with pulmonary function among European and African ancestries from the UK Biobank.Communications biology · 2023Article
- Genome-wide analysis of NBS-LRR genes revealed contribution of disease resistance fromFrontiers in plant science · 2023Article
- Whole genome sequencing reveals epistasis effects within RET for Hirschsprung disease.Scientific reports · 2022Article
- Can the "female protective effect" liability threshold model explain sex differences in autism spectrum disorder?Neuron · 2022Review
75 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
25 authors at 6 institutions in 6 countries.
Funding
Abstract
The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C-->T allele (rs2435357: p = 3.9 x 10(-43) in European ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 x 10(-5)) and familiality (p = 6.2 x 10(-4)). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.